Regulation of Adipose Tissue Plasticity by Pericyte GIPR - Project Abstract Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretins made in the gut and released in response to food intake. GIP is responsible for communicating with key metabolic tissues to govern the efficient uptake and metabolism of ingested nutrients. One key target for GIP is adipose tissue, which expresses the GIP receptor (GIPR) but not the receptor for the second incretin GLP-1, emphasize a potential differentiating mechanism of action between the two incretins. How GIP regulates adipose tissue metabolism in the postprandial state is not fully understood and complicating the interpretation of the published literature is a lack of consensus on which cell type is the target for GIP in adipose tissue. Contrary to the consensus view that the GIPR is expressed in adipocytes, we have generated several orthogonal data sets that implicate pericytes as the principal GIPR+ cell type in adipose tissue. Pericytes are specialized cells that line the vasculature with the ability to regulate several aspects of adipose tissue biology. Importantly, our preliminary data suggests that GIPR+ pericytes represent high-committed preadipocytes, suggesting an essential role in adaptive adipogenesis in response to various physiological or pharmacological inputs. Based on these data, we hypothesize that GIPR action in adipose tissue enhances pericyte activity in a manner that supports healthy adipogenesis, enabling the appropriate storage of excess energy in the context of overnutrition. We have generated several novel tools to test this hypothesis, including mouse models to support the identification and lineage tracing of GIPR+ cells, models with selective deletion of GIPR in pericytes, and pharmacological interventions that activate GIPR function. This MPI grant will leverage the expertise of both the Gupta (adipose) and Campbell (incretins) groups to thoroughly and rigorous execute the aims of this grant. Completion of this work has direct implications for understanding the physiology and pathophysiology of adipose tissue in response to weight gain, bring the importance of adipose tissue pericytes to the forefront, and provide mechanistic insight into pharmacology therapies that target the GIPR currently being employed to treat type 2 diabetes and obesity.
